The proposed research will explore the potential role of the mineralocorticoid receptor (MR) in the regulation of the hypothalamic-pituitary-adrenal axis (HPA) under conditions of stress. The HPA secretes increased cortisol or corticosterone (CORT) when an organism is confronted by stress, while secreting a low level of CORT during non-stress states. To prevent excessive activity of the axis, CORT negative feedback limits the operation of this hormone system. Negative feedback is mediated by two receptors for CORT: the glucocorticoid receptor (GR) and MR. Traditionally, GR is thought to control the HPA during a stress response and MR thought to control the HPA in non-stress, basal states. However, the role of MR might also be to regulate the HPA in stress situations. The role of MR may be especially important during milder stress. such as the challenges people face every day. If MR are not functioning properly because of experiential or congenital effects, an organism may show an increased HPA response to stress. Abnormal HPA function has been connected with depression, PTSD, and other psychopathologies. It is therefore relevant to better understand the role of MR in HPA control. To accomplish this, a range of stressor will be identified in which the HPA requires MR for normal control of the CORT response. This will be accomplished via treatment of animals with MR antagonists (e.g., RU28318), and then observing their CORT, ACTH, and CRH response to stress. Then, the interaction between MR and GR control of the HPA will be examined in several stressors of varying intensities. This will be done to better understand the exact nature of MR contribution to control of the HPA during stress. And finally, the role of MR in controlling HPA responding will be examined after a stressor has been experienced repeatedly, a situation previously shown to increase the number of brain MR.